Cells of the immune system in the brain--microglia and perivascular monocytes/macrophages--are a part of neuroimmunoendocrine system that regulates homeostasis. Dysregulation of this system in aging is proposed to be one of pathomechanisms in Alzheimer's disease (AD). Brain microglia and monocytes/macrophages are involved in production of amyloid plaques, and secrete factors that cause neurite degeneration and death of neurons. However, formation of amyloid in brain blood vessels by vascular smooth muscle cells takes place without apparent involvement of phagocytic cells. Microglia and monocytes/macrophages were shown to produce factors that regulate the production of beta-amyloid precursor protein (betaAPP) and B- amyloid peptide (Abeta) in cells of the central nervous system. This proposal is designed to test the hypothesis that monokines and prostanoids produced by microglia and monocytes/macrophages, decrease the production of Abeta in vascular smooth muscle cells, and thus have a protective activity against accumulation of Abeta and amyloid formation in blood vessel walls. This hypothesis will be tested by studying the influence of monokines and prostanoids on the metabolism of betaAPP and Abeta in our recently described model of cultured vascular smooth muscle cells (SMC). This influence will be tested in correlation with the engagement of SMCs in beta-amyloidosis: in cultures of SMCs (isolated from normal blood vessels) which do not accumulate Abeta, and in SMCs which accumulate Abeta as intracellular deposits--isolated from blood vessels with amyloid deposits, or induced to accumulate Abeta by treatment with apolipoprotein E. Specifically, the effects of IL-1, IL-3, IL-6, TNF-alpha, TGF-beta, PGE1, PGE2 and PGF2-alpha will be studied on production, processing secretion and intracellular distribution of betaAPP and secretion and accumulation of Abeta.